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Ca2+/Calmodulin-Dependent Protein Kinases in Leukemia Development

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Ca2+/Calmodulin-Dependent Protein Kinases in Leukemia Development https://www.scientificarchives.com/journal/journal-of-cellular-immunology Journal of Cellular Immunology Review Article Ca2+/calmodulin-dependent Protein Kinases in Leukemia Development Changhao Cui2, Chen Wang1, Min Cao1, Xunlei Kang1* 1Center for Precision Medicine, Department of Medicine, University of Missouri, 1 Hospital Drive, Columbia, Missouri 65212, USA 2School of Life Science and Medicine, Dalian University of Technology, Liaoning 124221, China *Correspondence should be addressed to Xunlei Kang; [email protected] Received date: March 18, 2021, Accepted date: April 20, 2021 Copyright: © 2021 Cui C, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Abstract Ca2+/ calmodulin (CaM) signaling is important for a wide range of cellular functions. It is not surprised the role of this signaling has been recognized in tumor progressions, such as proliferation, invasion, and migration. However, its role in leukemia has not been well appreciated. The multifunctional Ca2+/CaM-dependent protein kinases (CaMKs) are critical intermediates of this signaling and play key roles in cancer development. The most investigated CaMKs in leukemia, especially myeloid leukemia, are CaMKI, CaMKII, and CaMKIV. The function and mechanism of these kinases in leukemia development are summarized in this study. Keywords: CaMKII, CaMKI, CaMKIV, Leukemia, ITIM containing receptor, Signaling pathway, Therapeutic target Introduction The classic CaMKs include CaMKI, CaMKII, and CaMKIV, each of which has multiple isoforms. They Calcium (Ca2+) is an intracellular universal second are multifunctional serine/threonine protein kinases messenger that regulates a variety of cellular processes. that regulate the development and activity of different Many biological processes, including gene transcription, kinds of cell types through a variety of substrates [6-8]. cell cycle, migration, and apoptosis, are affected by changes The structure of CaMKs is critical for their activation in intracellular Ca2+ signaling [1,2]. Disruption of normal and regulation (Figure 1). Similarly, they all have an Ca2+ signaling can cause tumorigenic phenotypes [3]. N-terminal kinase domain, followed by a regulatory domain (consisting of Ca2+/CaM binding domain (CBD) 2+ Ca signaling works by forming a complex with calmodulin and auto-inhibitory domain (AID)). The ADP/ATP binding (CaM), a 148-amino-acid protein that transduces signals site locates between the small and large lobes of CaMKs’ 2+ 2+ in response to intracellular Ca elevation. Ca binding kinase domains. CaMKII, on the other hand, has a special significantly alters CaM’s conformation and enhances self-association domain at the C-terminus that allows it to its affinity for a wide range of CaM-binding proteins. form holoenzymes [8-10]. Since the discovery of CaM in 1970 as a Ca2+ regulator, there have been over 80 Ca2+/CaM-regulated protein CaMKs have a special phosphorylation-dependent kinases described [4]. However, based on their substrate mechanism for the regulation of kinase activity. specificity, not all CaM-regulated kinases are Ca2+/CaM- dependent protein kinases (CaMKs). For example, the The changes in intracellular Ca2+ concentration trigger once called CaMKIII is now termed eukaryotic elongation Ca2+ binding to the ubiquitously expressed CaM induces factor 2 (eEF2) kinase, due to containing a small number a conformational transition, which sparks its binding to of substrates [5]. CBD of CaMKs. The adjacent AID will then be released, triggering CaMK activation. The difference is, for CaMKII, Structure and Activation the Thr-286 residue in the regulatory domain is auto- J Cell Immunol. 2021 Volume 3, Issue 3 144 Cui C, Wang C, Cao M, Kang X. Ca2+/calmodulin-dependent Protein Kinases in Leukemia Development. J Cell Immunol. 2021; 3(3): 144-150. Figure 1: Schematic diagrams of CaMKII, CaMKI, and CaMKIV. The subunit structures with key residues involved in their regulation by phosphorylation (red font). See text for details. phosphorylated before kinase activation. While CaMKI/ of prostate cancer cells [18]. All these studies indicate CaMKIV is phosphorylated by an upstream kinase, CaMKs may be involved in different signaling pathways to CaMKK at Thr-177 and Thr-196 residue, respectively, manipulate cancer development. both located in the kinase domain. Despite the fact that CAMKK activates both CaMKI and CaMKIV, their distinct By using a variety of CaM antagonists or CaMKs specific subcellular distributions after phosphorylation, cytosolic inhibitors, the researchers have corroborated the roles of for CaMKI versus nuclear localization for CaMKIV, can CaMKs in a multitude of tumor types, which can prevent allow them to play different roles in distinct cellular cell growth, invasiveness, and /or metastasis [19-24]. For settings [9,11]. detail reviews on the role of CaMKs in cell migration and cancer metastasis, see [3,25-27]. CaMKs in Cancer Development Relevance to Leukemia Effective cell migration, which is critical for cancer metastasis, requires proper Ca2+ signaling control. Many In comparison to a large number of studies on CaMKs in CaMKs including CaMKI, CaMKII, and CaMKIV play a role neurology and solid tumors, research on CaMKs’ function in cell-migration-related cytoskeleton dynamics. Thus, the in controlling hematopoiesis and leukemia has been scarce. role of CaMKs in tumor cell invasiveness and metastatic Leukemia diseases are not classified as metastatic cancer. potential is well implicated [3,12]. Because they are thought to already be widespread when they are diagnosed. Below, we discuss the role of CaMKs in Iwatsubo’s group found that store-operated Ca2+ entry leukemia development based on work of ours and others. regulates melanoma proliferation and cell migration Emphasis is given to CaMK’s function in myeloid leukemia, by activating CaMKII. Further, they demonstrated that as well as the signaling pathway they are involved. CaMKII inhibition suppressed MAPK signaling pathway, which can inhibit human melanoma cell migration and Using the TCGA database of AML patients, we conducted metastasis in the lungs [3,13,14]. Interestingly, the CaMKII/ an in silico study of the relationship between gene MAPK signaling axis was also linked to colon cancer, expression and overall survival in AML patients. (https:// inhibiting CaMKII decreased cancer cell proliferation, tcga-data.nci.nih.gov/tcga/). The expression of most migration, and invasion [15]. The CaMKK pathway has CAMKs analyzed showed a negative correlation between been shown to promote cerebellar granule precursor expression and patient survival, which including CAMKI, migration and differentiation during normal cerebellar CAMK2A, CAMK2D, CAMK4, CAMKK2 [28,29]. These development via CaMKIV [16], while CaMKK/CaMKI results suggest that many CaMKs directly support human cascade regulates basal medulloblastoma cell migration leukemia cell growth. Here, we summarize the leukemia- via Rac1. In addition, pharmacological CaMKK inhibition related roles of individual CaMKs. blocks both estrogen-induced Rac1 activation and medulloblastoma migration [17]. These findings indicate CaMKII that the differential regulation of CaMKs in normal and malignant scenarios is context-dependent. McDonnell’s CaMKII is the most widely studied CaMKs, which consists group found that CaMMKβ is highly expressed in the of four homologous (CaMKIIa, CaMKIIb, CaMKIIg, and prostate and is further elevated in prostate cancers. Using CaMKIId) [1]. CaMKII’s autophosphorylation is one of its cellular models of prostate cancer, they demonstrated that most important functional characteristics which means CaMKK/AMPK regulates androgen-dependent migration that its activation is self-contained and less influenced J Cell Immunol. 2021 Volume 3, Issue 3 145 Cui C, Wang C, Cao M, Kang X. Ca2+/calmodulin-dependent Protein Kinases in Leukemia Development. J Cell Immunol. 2021; 3(3): 144-150. by Ca2+ concentration or calmodulin regulation. CaMKII of human CAMK1 mRNA expression in 43 human AML makes up about 1% to 2% of total brain protein, and samples showed that it is highly expressed in M5 AML numerous studies have shown that it plays an important cells [28,43]. Moreover, CaMKI is greatly expressed role in controlling neuronal cell growth and function [26]. in AML LSCs in mouse MLL-AF9 model. Gain-of- function and loss-of-function analyses of CaMKI in AML Although aberrant activation of CAMKII has been linked cells in vivo proved that CaMKI is essential for the growth to different hematopoietic malignancies [30,31], most of human and mouse AML cells [28,29]. The mechanistic studies focus on one of its isoforms, CaMKIIg, and its role studies indicated CaMKI participates in the Inhibitory in myeloid leukemia. CaMKIIg is preferentially expressed leukocyte immunoglobulin-like (ITIM) receptors signaling in myeloid cells [32,33]. Furthermore, the activation of axis in leukemia development by the recruitment of SH2 CaMKIIg is greatly increased in leukemia stem/progenitor domain-containing phosphatase1 (SHP-1). The activated cells but not in normal hematopoietic cells [34-36]. By CaMKI can be transported into the nucleus [44] and phosphorylating and inhibiting the transcriptional function activate the downstream transcription factor cyclic AMP of retinoic acid receptors (RARs), CaMKIIg prevents the element-binding
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